The ultimate goal of this R21 project is to evaluate the potential of white tea extract (WTE) for lung cancer chemoprevention. Whereas most of the work evaluating the anti-neoplastic effects of tea has been done on green tea, the potential health benefits of white tea and its advantage over green tea are becoming increasingly recognized. We therefore hypothesize that white tea extract can favorably modulate mechanisms associated with lung tumorigenesis, and may be useful for lung cancer chemoprevention. Specific Aim 1: To evaluate the anticarcinogenic effects of WTE against lung cancer. Specific Aim 1.1A: To examine effects of WTE on the induction of apoptosis in nonsmall cell lung cancer (NSCLC) and to further characterize the molecular mechanisms responsible for the WTE-induced apoptotic cell death. Specific Aim 1.1B: To determine the effects of WTE on the induction of apoptosis in an in vitro model of lung carcinogenesis. The differential effects of varying doses of WTE on apoptosis will be determined by comparing conditioned nonsmall cell lung cancer (NSCLC) cell lines to normal human bronchial epithelial (NHBE) cells. To explore the potential of WTE on preventing malignant transformation, similar experiments will be carried out using an in vitro model of lung carcinogenesis, comprised of BEAS-2B cells exposed to lung carcinogens. The ability of WTE to induce apoptosis in neoplastic cells (including 1198, a premalignant bronchial epithelial cell line) through activating PPAR- via an increase in 15-HETE production will be ascertained. Specific Aim 1.2: To evaluate the differential effects of WTE on cancer-relevant, pathway specific gene expression in NSCLC, BEAS-2B, 1198, and NHBE cells. In addition to inducing apoptosis, WTE may also favorably modulating multiple carcinogenic mechanisms. We will use Cancer PathwayFinder real time PCR array to detect differential alterations in cancer relevant, pathway specific gene expression by WTE in these cells. Specific Aim 1.3: To evaluate the differential effects of WTE on caspase 3 activities in NSCLC, BEAS-2B, 1198 and NHBE cells. Specific Aim 2: To evaluate the effects of WTE on arachidonic acid metabolism and PPAR- signaling pathway in an in vitro model of the lung microenvironment. To see if WTE will mediate changes in the lung microenvironment that may help prevent lung cancer, a surrogate model using coculture systems comprised of human bronchoalveolar lavage (BAL) cells with either NSCLC or NHBE, or 1198 or BEAS-2B cells will be used. The differential effects of WTE on arachidonic acid metabolism and PPAR- activation in the co-cultures will be assessed. Specific Aim 3: To evaluate the stability and metabolism of EGCG in our model systems to ensure that WTE-induced antineoplastic effects are not due to in vitro "artifacts." The findings of this proposed study will provide important insights into the anti-neoplastic properties of WTE in the lungs, and identify potential surrogate endpoint biomarkers for monitoring the efficacy of lung cancer chemoprevention trials with WTE in the future. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death in this country, surpassing deaths caused by colorectal, breast and prostate cancers combined;because of the dismal prognosis, safe, efficacious chemopreventive strategy for lung cancer is urgently needed. The purpose of this R21 application is to evaluate the anti- carcinogenic effects of white tea extract (WTE) on lung cancer, using a variety of in vitro model systems to simulate different stages of lung carcinogenesis, as well as the lung microenvironment. The findings of this preclinical application will provide novel, important insights into the anti-neoplastic properties of WTE in the lungs, and set the stage for clinical trials to determine the feasibility and efficacy of WTE for lung cancer chemoprevention in the future.